Osteoporosis is a major public health problem, which is mainly characterized by low bone mineral density (BMD). BMD has strong genetic determination with heritability >60%. During the past 9 years, we have accumulated unprecedented large samples. We are in a position to identify genomic regions underlying BMD variation with exceptionally high power and certitude using multiple and complementary approaches. We have recruited and phenotyped 4,259 subjects from 361 Caucasian pedigrees. All the subjects have been genotyped for 411 microsatellite (MS) markers throughout the whole human genome. We performed preliminary analyses for whole genome scan (WGS) and for genetic epistasis. Several genomics regions showing strong linkage to BMD were identified. In this project, we request support to 1) pursue sophisticated, thorough and comprehensive linkage analyses to investigate genetic heterogeneity (including imprinting), gene by gene (GxG) and gene by environment (GxE) interactions in our WGS analyses;2) genotype dense MS markers to saturate potentially significant regions (i.e., LOD scores >1.9) found in our WGS and re-analyze these regions with higher resolution and certitude;3) test linkage for markers that have shown at least suggestive linkage to BMD in earlier studies using our powerful large sample;4) perform focused analyses on our gene expression data (already obtained) within linkage regions identified in the above WGS analyses and perform RT-PCR, to infer positional and functional candidate genes;5) test most promising candidate genes identified/inferred from the above analyses for association with BMD variation in 800 Caucasian nuclear families (-700 nuclear families have already been recruited;recruitment of the remaining 100 families is being supported by an ongoing NIH grant and is expected to complete by Sept. 1, 2006. Identifying genomic regions and candidate genes for BMD variation with high certitude is important in unraveling genetic variants underlying risk of osteoporosis. It will form a solid basis for further fine mapping and association studies. It will expedite characterizing the mutations and the functional products underlying risk of osteoporosis, and help studies of interactions between genetic and environmental causes of osteoporosis. This knowledge is essential for the development of preventive interventions and/or cures for osteoporosis that may be based on individuals'specific genotypes.